In recent years, the causative genes of various diseases have been identified in quick succession, and a variety of therapeutic methods for such diseases have been studied and established. Of these methods, the most intensively studied are mostly therapeutic methods for complementing enzyme gene deficiencies. It has been reported that enzyme replacement therapy using “Cerezyme” (Genzyme) is effective for patients with Gaucher's disease, in which β-glucocerebrosidase is deficient, and that enzyme replacement therapy using “Aldurazyme” (Genzyme) is effective for patients with mucopolysaccharidosis, in which α-L-iduronidase is deficient. Previously attempted gene therapies include introducing the adenosine deaminase (ADA) gene to patients with ADA deficiency, and introducing the coagulation factor IX gene to patients with hemophilia B. In addition to enzyme deficiencies, a large number of genetic diseases are known, such as genetic diseases of cytokines and their receptors. Some patients with type II diabetes mellitus, which accounts for approximately 90% of diabetes mellitus cases, have been reported to have insulin receptor deletions or mutations. Such deletions and mutations are assumed to cause the disease. Furthermore, some patients with thrombocytopenia have been reported to have thrombopoietin receptor deletions and mutations, and the failure of TPO signaling can be thought to cause the disease. To date, no fundamental therapeutic methods have been available for such genetic diseases, and the establishment of such therapeutic methods is expected.
Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare disorder that causes thrombocytopenia in infancy and pancytopenia in later childhood. It has been revealed that TPO, a thrombopoietic growth factor, is present in CAMT patients at a high concentration in sera, but that platelets and hematopoietic precursor cells lack TPO responsiveness. Most of these patients have been found to carry point mutations in their thrombopoietin receptor (c-MPL) gene. It has also been reported that such mutations result in frame shift or insertion of a termination codon, leading to patients who have a total loss of thrombopoietin receptor function and patients who have a homozygous or heterozygous amino acid substitution in the extracellular domain of the receptor (see Non-patent Document 1). Bone marrow transplant is the only currently available therapeutic method for treating such patients.
[Non-Patent Document 1]
Matthias Ballmaier, Manuela Germeshausen, Harald Schulze, Klara Cherkaoui, Sabine Lang, Annika Gaudig, Stephanie Krukemeier, Martin Eilers, Gabriele Strausz, and Karl Welte, “BLOOD”, vol. 97, No. 1, pp. 139 (Jan. 1, 2001).